Allergy, Immunity and Tolerance in Early Childhood: The First Steps of the Atopic March

By Hugh A. Sampson

Allergy, Immunity and Tolerance in Early Childhood: The First Steps of the Atopic March provides valuable insights on the atopic diseases, including asthma, allergic rhinitis, atopic dermatitis, and food allergies, which have developed into major health problems in most parts of the world.

As the natural history of these chronic diseases has been extensively studied, including their major genetic, environmental, and lifestyle determinants and potential protective factors, the book presents tactics on how pediatric allergists can provide early intervention. In addition, the book unites key, global experts in the field who summarize their collective, and current, knowledge of the early stage of the "Atopic March", along with novel ideas for potential options of prevention.

• Summarizes the current knowledge of the epidemiological, genetic, and cellular basis of allergic diseases
• Ideal reference for the study of allergies in young children, atopic dermatitis, allergic rhinitis, childhood asthma, and food allergies
• Provides landmark findings in the field of immunology and allergy development
• Fulfills the need for a book that focuses on primary and secondary allergy prevention, especially during the first years of life
• Unites key, global experts in the field who summarize their collective, and current, knowledge, along with novel ideas for potential options of prevention

• Language: English
• Publisher: Academic Press
• Release date: Sep 10, 2015
• ISBN: 9780127999302

Book preview

Allergy, Immunity and Tolerance in Early Childhood

The First Steps of the Atopic March

Ulrich Wahn

Department of Pediatric Pneumology and Immunology, Charité University Medicine, Berlin

Hugh A. Sampson

Icahn School of Medicine at Mount Sinai, New York

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Introduction

1. The Maturation of Immune Function in Pregnancy and Early Childhood

Introduction

Immune development in health and disease

Interplay of innate and adaptive immune regulation in organ-specific responses

Key influences and determinants of early immune function and regulation

Modulating early immune development to promote immune regulation

Conclusion

2. Immunological Aspects of the Atopic March

Introduction

Global inventory of the developmental pattern of allergen-specific antibody

Tentative interpretation of phases observed in the serological picture

The trends of IgE levels to allergenic sources

Immunoglobulin E trends examined at a molecular level

Discussion

3. Atopic Dermatitis in Infancy and Childhood

Definition

Family history and genetics

Natural history of disease

Allergic sensitization and allergy as comorbidity

Rhinitis and asthma as comorbidity

Urticaria as comorbidity

Determinants of the disease

Key elements of treatment

Prevention

Long-term outcome in adulthood

4. Adverse Reactions to Food

Clinical presentation of food allergy in infancy

Epidemiology and natural course

Pathogenesis

Diagnostic

Therapy

Immunotherapy for food allergy

5. Viral-Induced Wheeze and Asthma Development

Introduction

Longitudinal studies of childhood wheezing

Etiology of wheezing illnesses in infancy

Risk factors for virus-induced wheezing

Progression from virus-induced wheezing to asthma

Do severe viral respiratory infections in infancy cause asthma?

Conclusions

6. Infantile Lung Function and Airway Hyperresponsiveness

Introduction

Lung development

Lung function measurements

Lung function development

Postnatal impact on lung function development

Factors that may influence in utero lung function development

Infantile AHR

Summary and conclusion

7. The Development of Allergic Rhinitis in Childhood

Incidence

Period prevalence

Sex differences

Comorbidity

The role of sensitization

Early predictors

Protective factors

Principles of therapy

Options for prevention

8. Genes and Atopic Phenotypes

Introduction

Tools for disentangling the genetics of atopy

Do genes co-associated with multiple childhood atopy phenotypes represent atopic march candidate genes?

Summary and conclusions

9. Epigenetic Factors Before and After Birth

Introduction

Principles of epigenetic mechanisms

Epigenetics in T-cell development as a decisive mechanism for allergy development

Epigenetic control in fetal immune development

Environmental factors and epigenetic modifications in early allergy development

Allergens as triggers for Th2 responses are associated with epigenetic modifications in target cells

Microbes in the human environment are capable to protect against allergy development via epigenetic mechanisms

Airborne, xenobiotic exposures act though epigenetic modulation and enhance early allergic development

Dietary and metabolic factors are capable to modify epigenetic programs

Conclusion

Abbreviations

10. The Physiological Induction of Tolerance to Allergens

Introduction

Mechanisms of oral tolerance

Mechanisms of airway tolerance

Mechanisms of action of iTreg in mediating oral and airway tolerance

Early-life exposures can influence immune programming of tolerance

Summary

11. Microbiome and the Effect on Immune Response

Introduction

Coevolutionary interdependency of the microbiome and the immune system

Microbiome acquisition and development

Effects of the microbiome on immune development

Influence of the microbiome on allergy development

Future perspectives

12. Indoor Allergen Exposure

Pet exposure

Preventive measures reducing pet allergen exposure

House dust mite

House dust mite avoidance

Cockroaches

Molds

Other allergens

Summary

13. Microbial Influences on the Development of Atopy

14. Role of Vaccines

Introduction

Allergens that may be contained in vaccines

Allergic immune responses to vaccines

Immunization and development of allergy

Considerations for some specific vaccines

Diagnostic aspects

Identification of patients at heightened risk

Immunization of patients at heightened risk

Conclusion

15. Breast—Always Best?

Introduction

Historical aspects

Challenges with studies

Evidence for breastfeeding in allergy prevention

Possible mechanisms by which breastfeeding may protect against allergies

Impact of maternal interventions during breastfeeding on prevention of allergy

Conclusions

Abbreviations

16. Dietary Interventions in Infancy

Introduction

The gut, the diet, and oral tolerance in early life

Allergens in the diet: from avoidance toward tolerance induction

Immunomodulation via dietary interventions

Conclusion

Abbreviations

17. Allergen Exposure and Avoidance as Part of Early Intervention and Prevention

Allergen avoidance

Allergen exposure, sensitization, and disease

House dust mite allergen avoidance in primary prevention

Avoidance of other allergens

Why environmental allergen avoidance in primary prevention is not effective

Secondary avoidance

Studies involving moving patients to a sanatorium or hospital

Secondary allergen avoidance by making changes in the patient’s own home

18. Pharmacotherapies Early in Life to Prevent the Atopic March

Introduction

Adverse effects of pharmacotherapies on allergy outcomes

Prevention strategies

Conclusions

19. The Role of Antiviral Strategies for the Prevention of Childhood Asthma

Introduction/Background

General antiviral strategies to consider

Lessons learned from antiviral strategies focused on RSV

Antiviral strategies for rhinovirus

Specific antivirals

Asthma exacerbations provoked by rhinovirus in the atopic population

Conclusions

20. Prevention of Allergy/Asthma—New Strategies

Introduction

Asthma initiation during childhood

21. Antiallergic Strategies: Induction of Tolerance to Food

Introduction

Definition of oral tolerance

Immunological mechanisms of oral tolerance

Clinical phenotypes of oral tolerance

Risk and protective factors for food allergy

Tolerance induction in the prevention of food allergy

Allergen-specific immunotherapy in the management of food allergy

Conclusion

Index

Copyright

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List of Contributors

Rob C. Aalberse,     Department of Immunopathology, Sanquin Blood Supply Foundation and the Landsteiner Laboratorium, Academic Medical Centre, Amsterdam, The Netherlands

Birgit Ahrens,     Department of Pediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany

Katrina Allen,     Food Allergy, School of Inflammation and Repair, University of Manchester, Murdoch Childrens Research Institute, The Royal Children’s Hospital, Flemington Road Parkville, Victoria, Australia

Hasan Arshad

Allergy & Clinical Immunology, Clinical & Experimental Sciences, University of Southampton, Southampton, UK

David Hide Asthma and Allergy Centre, St. Mary’s Hospital, Isle of Wight, UK

Kathleen C. Barnes,     The Johns Hopkins Asthma & Allergy Center, Baltimore, MD, USA

Karl E. Bergmann,     Department of Obstetrics, Charité University Medicine, Berlin, Germany

Renate Bergmann,     Department of Obstetrics, Charité University Medicine, Berlin, Germany

Kirsten Beyer

Department of Pediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany

Icahn School of Medicine at Mount Sinai, New York, NY, USA

Bengt Björkstén

Institute of Environmental Medicine, Karolinska Institutet, Stockholm

School of Health and Medical Sciences, Örebro University, Sweden

Amaziah Coleman,     Departments of Pediatrics and Medicine, University of Wisconsin-Madison, Madison, WI, USA

B.C.A.M. van Esch

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Department of Immunology, Danone Nutricia Research, Utrecht, The Netherlands

J. Garssen

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Department of Immunology, Danone Nutricia Research, Utrecht, The Netherlands

James E. Gern,     Departments of Pediatrics and Medicine, University of Wisconsin-Madison, Madison, WI, USA

L. Grabenhenrich,     Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medicine, Berlin, Germany

Christoph Grüber,     Department of Pediatrics, Klinikum Frankfurt (Oder), Frankfurt (Oder), Germany

Peter W. Heymann,     Division of Pediatric Respiratory Medicine/Allergy, Asthma and Allergic Diseases Center, University of Virginia, Charlottesville, VA, USA

Patrick Holt,     Telethon Kids Institute, The University of Western Australia, Perth, Australia and Queensland Children’s Medical Research Institute, The University of Queensland, Brisbane, Australia

Kirsi M. Järvinen,     University of Rochester Medical Center, Pediatric Allergy and Immunology, Rochester, NY, USA

Maria C. Jenmalm,     Department of Clinical and Experimental Medicine, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, Sweden

T. Keil,     Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medicine, Berlin, Germany

L.M.J. Knippels

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Department of Immunology, Danone Nutricia Research, Utrecht, The Netherlands

M.V. Kopp,     Department of Pediatric Pulmonology, Clinic for Pediatric and Adolescent Medicine, University Luebeck, Luebeck, Germany

A.I. Kostadinova

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Department of Immunology, Danone Nutricia Research, Utrecht, The Netherlands

Gideon Lack,     Clinical Academic Paediatric Allergy Service, Guy’s & St. Thomas’ NHS Foundation Trust, Children’s Allergies Department, St. Thomas’ Hospital, London, UK

Susanne Lau,     Department of Pediatric Pneumology and Immunology, Charité, University Medicine, Berlin, Germany

Karin C. Lødrup Carlsen

Department of Paediatrics, Oslo University Hospital, Oslo, Norway

University of Oslo, Oslo, Norway

Paolo M. Matricardi,     Department of Pediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany

Erika von Mutius,     Dr. von Hauner Children’s Hospital of Ludwig, Maximilian University of Munich, Munich, Germany

Martin Penagos,     Allergy and Clinical Immunology Department, Royal Brompton Hospital and Imperial College London, London, UK

Petra Ina Pfefferle,     Comprehensive Biomaterial Bank Marburg CBBM, Centre for Tumor and Immunobiology, Philipps-University Marburg, Marburg, Germany

Thomas Platts-Mills,     Asthma and Allergic Disease Center, School of Medicine, University of Virginia, Charlottesville, VA, USA

Susan L. Prescott,     School of Paediatrics and Child Health, Telethon KIDS Institute, University of Western Australia, Princess Margaret Hospital, Perth, WA, Australia

Harald Renz,     Institute for Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps-University Marburg, Marburg, Germany

Hugh A. Sampson,     Icahn School of Medicine at Mount Sinai, New York, NY, USA

Alexandra Santos,     Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, London, UK

Bianca Schaub,     Pediatric Pulmonary Division, University Children’s Hospital Munich, LMU Munich, Munich, Germany

Jonathan M. Spergel,     The Children’s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, PA, USA

Mimi L.K. Tang

Department of Allergy and Immunology, The Royal Children’s Hospital, Melbourne, VIC, Australia

Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia

Department of Paediatrics, University of Melbourne, VIC Australia

Ronald B. Turner,     Division of Pediatric Infectious Diseases, University of Virginia, Charlottesville, VA, USA

M.M. Vonk

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Department of Immunology, Danone Nutricia Research, Utrecht, The Netherlands

U. Wahn,     Department of Pediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany

John O. Warner,     Research for the Women and Children’s Clinical Program Group, Imperial College, London, UK

T. Werfel,     Department of Dermatology and Allergology, Hannover Medical University, Hannover, Germany

Magnus Wickman,     Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden

L.E.M. Willemsen,     Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Robert A. Wood,     Johns Hopkins University School of Medicine, Baltimore, MD, USA

Introduction

One understands life only backwards; to live, you must do it forwards.

Søren Aabye Kirkegaard

The term allergic march refers to a characteristic sequence of phenotypic changes of various manifestations in infancy, childhood, and adolescence that seem to be coexpressed or genetically linked. Despite a wide range of variation in individual patterns of comorbidity, there appears to be a common developmental pattern including:

1. a sequence of individual immunoglobulin E responses starting with cow’s milk and hen’s egg proteins, followed by indoor and outdoor allergens

2. a sequence of clinical symptoms starting with eczema, which may be followed by rhinitis and asthma. In most cases, the first atopic manifestations can be observed in early infancy. The natural history of the disease has been carefully evaluated over the past two decades by various researchers. They have provided a remarkable gain in knowledge regarding the earliest changes during pregnancy and their predictive value, the role of genes, environmental exposure to allergens, microbial products and pollutants, and lifestyle and the role of the microbiome.

As it has turned out, atopic diseases have become a major health problem in childhood in many affluent countries, forcing general pediatricians and primary care physicians to come to terms with them. The burden of atopic diseases is frequently dramatic and the cost of health care to deal with this problem in many countries is highly relevant.

Currently, atopic manifestations represent a challenge for the pediatric allergist, who is not only responsible for early diagnosis and treatment, but has also a long-lasting interest in concepts for primary prevention. A number of highly interesting studies in animal models have led to promising concepts; unfortunately, only a few of them have been confirmed in humans. In this book, top experts in the field have been invited to contribute; presenting an update on accumulated knowledge of the natural history of the disease, as well as hopes and disappointments surrounding allergen-specific or nonspecific early interventions, including studies of microbial products. Not least in its achievement, this book outlines gaps in knowledge and presents novel hypotheses that might stimulate research and patient care in years to come.

Ulrich Wahn

Hugh Sampson

1

The Maturation of Immune Function in Pregnancy and Early Childhood

Bianca Schaub∗,  and Susan L. Prescott§     ∗Pediatric Pulmonary Division, University Children’s Hospital Munich, LMU Munich, Munich, Germany     §School of Paediatrics and Child Health, Telethon KIDS Institute, University of Western Australia, Princess Margaret Hospital, Perth, WA, Australia

Abstract

Healthy immune development usually occurs with no intervention being based on the efficient interaction of innate and adaptive immune mechanisms. Environmental exposure interacting with a given genotype participates in shaping early immune maturation toward favorable, healthy development since the evolution. Certainly, microbes are one of the most relevant and abundant constituents of the environment. Any effects of microbial compounds stimulating innate immunity are based on a variety of factors including age, the host's genetic background, and additional environmental factors. Whereas the mucosa and epithelium are critical as the first contact site for microbes, the gut is particularly important as an organ with continuous exposure to microbial substances. Although the microbiota have emerged as arguably as the single most important factor in normal immune development, we know little about how this relationship evolves in pregnancy and how we can use it to prevent allergy and other noncommunicable diseases. In particular, we need to further explore the relationship between maternal gut flora in pregnancy and immune development. A better insight into the underlying mechanisms of immune response by exposure to microbes may result in novel therapeutic and preventive strategies that are relevant for different immune-mediated diseases including allergies. However, a critical issue will be to combine beneficial control of healthy immune mechanisms without suppressing other defense mechanisms against harmful microbes, other immune-mediated diseases, or cancer.

Keywords

Adaptive; Childhood; Immune; Innate; Maturation; Microbiome; Pregnancy

Introduction

The first 1000  days has become a core focus and a prominent catch phrase in growing efforts to understand the developmental programming of disease predisposition in early life. Spanning all aspects of health, the strong concept of the developmental origins of health and disease is based on clear evidence that events and exposures in early development can have lasting and sometimes latent effects on later health.¹,² Although the early focus of this research was on later-onset cardiometabolic diseases, it is clear that earlier-onset noncommunicable diseases (NCDs) such as allergic diseases share similar risk factors and should be regarded as a core part of this agenda.³ Understanding the early environmental influences on early immune development is also a key element in disease prevention.

The immune system has a critical role in the development, homeostasis, and function of virtually all organ systems. Subtle early variations in the pattern of immune response can predispose to disease and influence both the propensity and the dynamics of inflammation in later life.⁴ The modern epidemic of infant allergic disease has drawn considerable attention to the importance of early immune development and the potential impact of modern environmental changes on the maturing immune system. In addition to its obvious role in the rising predisposition to allergic and autoimmune disease, early immune dysregulation is now implicated in a range of NCDs, including predisposition to mental health disorders and cardiovascular disease.³,⁵ With economic prosperity and lifestyle changes, the rising propensity for inflammation is implicated in the rising burden of chronic disease and all-cause mortality in modern societies. It is therefore critically important to understand the normal processes and pathways that underpin the normal immune development, how these are modified by adverse early environmental exposures to lead to disease, and how these may be favorably modified to reduce that risk. Optimizing immune health in early life will reduce the risk of allergy and immune diseases, but it is also likely to reduce the burden of many other chronic inflammatory diseases. Because immune function is so responsive to the early environment, and because immune disease manifests so early, this provides an important early indicator for the effects of environment on human health.

Immune development in health and disease

Healthy immune maturation depends on efficient communication between the two pillars of immune regulation, the innate and adaptive immune systems, which are composed of a large number of involved cells (details are given in Ref. 6).

In brief, innate immune cells such as monocytes, granulocytes, dendritic cells (DC), natural killer (NK) cells, mast cells, thrombocytes, and locally relevant cells (e.g., pulmonary alveolar macrophages) are present during healthy immune maturation and are mostly active in some allergy-affected organs such as, for example, the skin and the respiratory tract.⁷

In addition, innate lymphoid type 2 cells, NK2 subsets, and regulatory NK and NK22 cells were shown to be involved in functional T cell responses, the production of immunoglobulin E (IgE), and the function of the epithelial cell barrier, are thus possibly involved in allergy development.⁸,⁹ Also, precursors of innate bone marrow-derived mucosal DC and the NLRP3 inflammasome may be involved in either inflammatory signaling cascades after virus infections or airway inflammation,¹⁰ both of which are relevant for allergy development.

In close connection with innate immunity, the key players of adaptive immune regulation, namely different T cell subpopulations composed of Th2, Th1, and Treg but also Th17, Th9, and Th22, and CD8+ cells, B cells, and regulatory B cells, are critical for healthy immune maturation and thus protection against allergic diseases.⁷

Early life immune regulation

The prenatal period is instrumental in shaping a child’s immune system (programming) influenced by a wide variety of factors elucidated below, including microbiome, nutrition, smoke exposure, and infection, among many others (Figure 1). This window of opportunity is thus critical for a wide range of risk and protective influences discussed in more detail below. Multifaceted effects on early immune programming can occur prenatally that are critical for effects on local tissues and relevant for risk for or protection from immune-mediated diseases, which may occur only several years later. Thus, an efficient interplay between innate and adaptive immune regulation can shape the maturing immune system, keeping it balanced over numerous years during childhood. Any default regulation affecting solely parts of the system or even cells can result in different immune-mediated diseases such as infections, more chronic diseases such as, for example, allergies, autoimmune diseases, or lack of tolerance.

Whereas bidirectional interactions between the fetus and mother seem critical for postnatal immune regulation, human studies on causal effects are complex because of multifaceted influences that are difficult to study at this time of maturation.

In addition to genetic factors such as immutable footprints, epigenetics, the environment, and their interactions influence early immune programming, subsequently affecting anatomical structures such as the mucosa and epithelium, and influencing barrier function.

Figure 1  Influences on prenatal and postnatal immune programming for the development of allergic diseases.

A wide range of environmental factors acting prenatally and/or postnatally are known to influence the maturation of immunological competence combined with genotype and epigenetics, and hence to modulate the risk for the development of allergic diseases. Reproduced with permission from Holt, Sly, Prescott, 2011. Early life origins of allergy and asthma (Figure 3). In: Stephen T., Holgate, Martin K., Church, David H., Broide, Fernando, D. (Eds.), Allergy: Principles and Practice, fourth ed. Elsevier Inc., Martinez.

The exact nature underpinning intrauterine modulatory mechanisms may be composed of the following: Although the amniotic fluid has been shown not to be sterile, direct and indirect modulation via fetoplacental transfer may occur. Decidual tissue maternal immune cells including macrophages, CD8+ and γδ-T cells, and large granulated lymphocyte cells are able to induce rejection of paternal histocompatibility antigens. Maternal–fetal tolerance to paternal alloantigens is actively mediated, involving pTregs (peripheral Tregs) distinctly responding to paternal antigens for tolerance induction.¹¹ Generally, maturation of the infant adaptive immune system occurs from the 15th to 20th week of gestation and can be Ag-specific.

Postnatal immune maturation influences are comparable to before birth, with the major difference in the absence of direct maternal environment. Whereas effects on immune programming most likely happen continuously with different thresholds on several types of immune cells, numerous factors induce changes directly in the organs subsequently affected by later disease. For allergic diseases, for example, airway antigen-presenting cells are most likely involved in local damage during airway inflammation and are critical to programming of adaptive T cell responses after migration to the lymph nodes.

Regarding innate priming, children during the first year of life are not present in the airways without an inflammatory trigger.¹² During respiratory infection, mature DCs are revealed,¹³ indicating that local pulmonary inflammation can influence DC maturation followed by T cell activation.

Although early respiratory tract infections (e.g., rhinovirus-induced) are linked to allergic inflammation, this early priming in the airways seems to be specific to the infectious agent.¹⁴ Taken together, early childhood exposure to infectious agents affects immune programming, locally and systemically, inducing immune networks and subsequently influencing Tregs and Th1/Th2 cell fate that is important for healthy immune balance. It is still unknown which type of infections in the skin and upper and lower respiratory tract are important for immune programming. Different viruses or bacteria in close interaction with genetic, epigenetic, and environmental factors may influence early immune maturation in distinct ways, either predisposing for disease development or protecting against it.

Interplay of innate and adaptive immune regulation in organ-specific responses

The nasopharyngeal tract, extending via the glottis and trachea to bronchi and bronchioli of the lung, exerts an efficient defense system against the multitude of airborne pathogens to which it is regularly exposed.⁶Innate immunity acts via mechanical, physical, and chemical barrier functions, fighting against invading microorganisms. Its main goal is to decide between innocuous and hazardous microorganisms, avoiding invasion of particles larger than 5  μm into the upper airways.

Regarding the skin, innate mechanisms regulate via the inflammasome and influence thymic stromal lymphopoietin induction; antimicrobial peptides and human β-defensins are involved in the pathophysiology of allergic skin diseases.¹⁵,¹⁶

Whereas adaptive immune regulation is closely linked to innate mechanisms, its onset happens in a slower fashion, needing a few days for efficient defense. Induction through cellular activation after innate immune regulation occurs primarily for respiratory tract infections. Here, humoral and mucosal immune regulation is important in parallel to T cell–induced immunity.

In this context, childhood asthma as a complex multifaceted disease entity characterized by inflammation, airway remodeling, and airway hyper-responsiveness is currently viewed as a syndrome with distinct disease entities.⁶ Different endotypes describing distinct functional mechanisms are likely to be mediated by different innate-adaptive interplay, critically influenced during early immune maturation.

Although Treg are now described as critical players in the pathophysiology of allergic asthma, their dysregulation is associated with predisposition to respiratory infections early in life, with deficient IgE class-switch and reduced induction of tolerance.¹⁷

At birth, decreased Treg numbers were associated with increased asthma risk, whereas increased Tregs were linked to protection from asthma.¹⁸,¹⁹ This asthma-protective effect via Tregs was persistent at age 4  years in the European PASTURE birth cohort.²⁰ In parallel, Tregs protected against allergic sensitization early in life (first year) in a high-risk asthma cohort in the United States, associated with an increase in Tregs after allergic sensitization and eczema as a potential counterregulation.²¹ In the German Cross-sectional Childhood Asthma Study, allergic asthma was associated with increased Tregs during manifestation of disease, pointing to a potential feedback mechanism to control inflammation.²² Extending this, nonallergic asthma was induced by neutrophilic Th17-shifted immune regulation.²²

Relevant for immune maturation, some childhood asthma phenotypes are actually similarly present in adults, such as eosinophilic and neutrophilic asthma, among others.²³ Adult asthma has been further characterized by Th2 high and low phenotypes, by measuring POSTN (periostin), CLCA1, and SERPINB2 in airway epithelial brushings or interleukin (IL)-4, IL-5, and IL-13 in sputum cells.²⁴ This has not yet been confirmed in children, but it accounts for different maturational effects among children and adults.

Taken together, multifaceted regulation of innate and adaptive immune mechanisms is relevant for asthma development and may be distinct for different asthma phenotypes.

Key influences and determinants of early immune function and regulation

A broad range of factors can influence patterns of immune development during the first 1000  days, and possibly even before this. Each of these, discussed in turn below, may have differential effects at different stages of development, and some may even be important before conception through the effects of parental health. Relatively little is known about potential transgenerational effects of environmental exposures in humans, although animal models have elegantly demonstrated that grand-maternal environmental exposures can be potentially inherited through epigenetic modifications.²⁵ This includes genes that predispose to the allergy/asthma phenotype. Although the significance of this is not known, it highlights the growing complexity of investigating the impact of a changing environment on the risk of disease.

In addition to direct effects on immune maturation, many types of environmental exposure implicated in the risk of allergic disease, such as nutrition, the microbiome, and pollutants, also affect the development and function of many organ systems. This may contribute to the organ-specific manifestations of disease. It may also explain the highly variable expression of disease, because a large and diverse range of genetic polymorphisms may contribute to differential vulnerability of different tissues and immune pathways in different individuals.

Genetic factors

Although familial predisposition has been well documented for allergic diseases, the multifactorial nature of these conditions has made it difficult to identify specific genes with genetic polymorphisms that have either clear causative effects or predictive value. Similarly, although a large number of genes have been identified in Genome Wide Association Studies (GWASs) on asthma, there is wide variation among individuals and between populations, which explains between 35% and 95% of the heritability of asthma.²⁶ In part, this appears to be caused by complex interactions with environmental exposures and variable effects according to the environmental setting. This has been well demonstrated with genetic polymorphisms linked to early immune function. A well-described example is seen in genetic variants in the innate Toll-like receptor (TLR)-related microbial receptor for endotoxin, CD14. Specifically, the CC allele has been associated with an increased risk of allergic disease, but only in children living in environments with low microbial burden.²⁷,²⁸ In a high microbial environment, carrying the CC allele has the opposite effect and appears to increase the risk of allergic disease.²⁹,³⁰ This indicates that the effects of specific genetic polymorphisms can depend on the environment and similarly appear to vary with a wide range of potential environmental exposures (such as smoking, other pollutants, and specific dietary nutrients).

However, some current studies point to the importance of distinct polymorphisms for diagnosis and treatment strategies in childhood asthma, For example, a new susceptibility gene, CDHR3, and four previously reported asthma susceptibility loci (GSDMB, IL33, RAD50, and IL1RL1) were associated with severe, recurrent exacerbations in the Danish COPSACexacerbation cohort, with substantially larger effect sizes than in previous asthma GWASs.³¹

Thus, whereas early measures of immune function in early childhood have been associated with both genetic polymorphisms and a familial history of allergic disease, many other factors in early life influence immune development. With advances in precision (personalized) medicine, it is hoped that genetic markers may better predict both disease risk and specific vulnerability to environmental risk factors; this is still out of reach with the current technology.

Direct effects of maternal allergy on immune maturation

Whereas familial allergy risk indicates a clear role for genetic risk, maternal immune phenotype may have direct effects on early immune programming. This is based on observations that maternal allergy is a stronger determinant of allergic risk than paternal allergy³²–³⁴ and that maternal allergy may also contribute more strongly to reduced neonatal Th1 interferon (IFN)-gamma responses associated with allergic risk.³⁵ This suggests direct maternofetal interactions in utero or other maternally imprinted effects. There is some evidence that allergic women have modified immune interactions with the fetus in pregnancy, with lower Th1 IFN-gamma responses to human leukocyte antigen-DR mismatched fetal antigens compared with nonallergic women.³⁶ These factors may affect the cytokine milieu at the maternofetal interface and could be implicated in the attenuated neonatal Th1 responses observed commonly in infants of atopic mothers,³⁷ a recognized risk factor for infant allergic disease.³⁸–⁴⁰ This suggests that the endogenous effects of the maternal allergic phenotype may compound the increasingly proallergic exogenous environment. The rise in maternal allergy may become a compounding factor in the rising rates of infant allergy, amplifying the effect of environmental changes and potentially influencing the age of onset, phenotype, and severity of disease in her offspring.

Maternal environmental exposures and immune maturation

Most environmental risk factors implicated in the allergy epidemic have demonstrated effects on early immune development, beginning in utero. This includes microbial exposure, early nutritional patterns, smoking, and other environmental pollutants, with demonstrated effects on both animal models and human observational and/or intervention studies.⁴¹,⁴²

Microbial exposure is arguably the strongest environmental stimulus for immune maturation, particular of regulatory and Th1 adaptive responses. Whereas most studies investigating the early immunomodulatory mechanisms have focused on postnatal microbial exposure, it is increasingly clear that the maternal microbial environment during pregnancy is also important in early immune programming.⁴³–⁴⁶ In normal healthy pregnancies, microbes can be detected in amniotic fluid,⁴⁷,⁴⁸ placental⁴⁸ and fetal membranes,⁴⁸,⁴⁹ cord blood,⁵⁰ and meconium.⁵¹–⁵³ This reveals that the womb is not sterile after all, and that antenatal microbial exposure provides an important initial source of immune stimulation for the fetus. Experimental models confirm that exposure to bacterial endotoxin, probiotic bacteria, or other apathogenic bacteria has immunomodulatory effects and protects the offspring against an allergic phenotype.⁵⁴–⁵⁶ These effects appeared to be mediated by activation of maternal innate (TLR) pathways,⁵⁶ with associated epigenetic effects on the regulation of Th1 gene expression in the newborn offspring.⁵⁷

Bavarian farmhouses provide one of the best natural experiments to see the effects of microbial exposure on humans.⁴³,⁵⁸,⁵⁹ Children growing up in this setting have a reduced risk of allergic disease,⁶⁰ and antenatal exposure affords greater protection from allergy than postnatal exposure alone.⁵⁸,⁵⁹ Biological data collected from cord blood samples also support this antenatal effect. At birth, newborns from farming families have increased numbers and function of regulatory cells (Treg) and lower type 2 immune responses.¹⁹ At age 4, Treg function is still more efficient in farm milk–exposed children, which points to a strong persisting effect during immune maturation.²⁰ They also show higher Th1 responses, which are likely to be important for suppressing the development of allergy in the critical period after birth.⁶¹ Most of these protective effects, most particularly against asthma, appear to result from contact with cows and straw and consumption of unpasteurized farm milk⁶²—all major indicators of the high microbial diversity that characterizes the farm environment. Furthermore, prenatal farm exposure was associated with a distinct epigenetic methylation pattern of asthma- and allergy-related genes such as genes from the ORMDL family, RAD50, IL13, and IL4.⁶³ Thus, part of the farm effect may be mediated by epigenetic regulation.

Maternal nutrition has another significant influence on immune development and allergy risk.⁶⁴–⁶⁶ Both specific nutrients and common dietary patterns have major effects on all aspects of fetal development, including immune function. A particular dietary pattern that has shown protection from allergy and other NCDs is the Mediterranean diet. Protection against childhood wheezing and other allergic manifestations⁶⁷–⁶⁹ may be related to higher levels of fiber, omega-3 polyunsaturated fatty acids (n-3-PUFA), and antioxidants in fresh fruits and vegetables (vitamins A, C, and E) and prebiotics,⁶⁶ all of which may have direct effects on immune function and anti-inflammatory effects on tissues. In particular, we have shown how increasing n-3-PUFA levels of diets in both pregnancy⁷⁰ and infancy⁷¹ can have favorable effects on infant immune function (increasing Th1 responses and reducing Th2 responses).

Adverse exposures in pregnancy may also influence fetal immune development, the most obvious and well-studied of which is maternal smoking, with toxic effects on placental function and many aspects of fetal growth and development. This includes specific effects on lung growth and asthma risk⁷² and on immune function.⁷³,⁷⁴ Oxidative stress produced by cigarette smoking and air pollution can have significant epigenetic effects including remodeling of proinflammatory genes.⁴² Mice exposed to diesel exhaust particles show an increased production of IgE with associated underlying epigenetic effects.⁷⁵ In humans, exposure to traffic particles in pregnancy has also been associated with epigenetic changes and has increased risk of developing asthma symptoms in children.⁷⁶ The many thousands of modern chemicals and pollutants that contaminate modern homes, food, clothing, and water sources, accumulating in human tissue with age, also may have adverse effects on human immune development,⁷⁷,⁷⁸ although this is still ill-defined. Notably, many of these and other contaminants have been associated with epigenetic effects⁷⁹,⁸⁰ including effects on global deoxyribonucleic acid methylation patterns at the low-dose exposure found in the ambient environment.⁸¹

A number of other exposures in pregnancy are also likely to influence immune function (reviewed elsewhere⁶⁵), including maternal stress and hypothalamic–pituitary–adrenal activation, which are closely linked to placental and immune function. Medications commonly used in pregnancy, such as antacids, reflux medications, paracetamol, and antibiotics,⁸²–⁸⁴ may carry an increased risk of some allergic diseases. Finally, there are emerging possible risk factors for allergy that are of uncertain significance, including higher risk of asthma in children conceived by in vitro fertilization.⁸⁵ Although this can be partly explained by the higher risk of neonatal complications, lower parental fertility appears to be a factor.⁸⁵ This could implicate a range of other modern environmental factors contributing to changes in reproductive health. All of these relationships serve to highlight the importance of the in utero environment in early immune programming as an essential prelude to environmental encounter after birth, shaping many other aspects of development and future health.

Early postnatal exposures and immune maturation

The concept of a window of tolerance came from observations that introducing complementary feeding before 3–4  months or after 6  months of age has been associated with increased allergy risk.⁸⁶ This is based on only observational data rather than controlled clinical trials, but it has led to concepts such as: (1) regular exposure to ubiquitous proteins such as foods and other innocuous environmental proteins may be part of developmental processes that promote subsequent clinical tolerance; and (2) factors such as immature gut barrier, gut inflammation, or less tolerogenic conditions during initial allergen encounter may lead to disruption of normal tolerance mechanisms. For this reason, there is great interest in conditions in the early postnatal environment that are most likely to promote or disrupt a tolerogenic milieu, particularly in the infant gut. In this regard, breastfeeding and infant dietary patterns (discussed further in Chapters 16 and 17) are particularly important because of direct influences on postnatal immune maturation and secondary effects on colonization patterns.⁶⁶,⁸⁷,⁸⁸ Other risk factors such as atopic dermatitis (Chapter 3) may increase the risk of early transcutaneous sensitization through an immature skin barrier.⁸⁹

After birth, the gut is the major interface between the host immune system and the microbial environment as a major driver of Th1 and Treg maturation. Thus, perinatal factors that modify colonization during this early period have been implicated in the rise of allergic disease, including caesarean section, use of antibiotics, and the diversity of the maternal microbiome.⁹⁰ Reduced diversity in the first month of life is associated with an increased risk of a range of allergic outcomes,⁹¹–⁹⁴ which suggests early effects on immune maturation. There is also preliminary evidence that reduced diversity (in infants delivered by caesarean section) and delayed Bacteroidetes colonization are associated with reduced Th1 responses in the first 2  years of life.⁹⁵ In parallel, increased diversity of food within the first year of life might have a protective effect on asthma, food allergy, and food sensitization and is associated with increased expression of a marker for regulatory T cells.⁹⁶ In contrast, children living in a high microbial environment (e.g., exposed to farm milk during early life) show increased Treg activity and lower risk of asthma as they approach school age.²⁰

Colonization of the upper gastrointestinal is also of emerging importance. In traditional environments, colonization with Helicobacter pylori occurs during infancy, from around 4–6  months of age, and persists unless eradicated with antibiotic treatment. These bacteria are emerging as important initiators of immune regulation in the upper gastrointestinal tract,⁹⁷ favoring immune tolerance to evade our innate and adaptive immune responses. This allows them to remain in their habitat for decades while conferring host benefit—inhibiting autoimmune and allergic T cell clones and protecting against allergies, asthma, and inflammatory bowel diseases,⁹⁸ particularly with early colonization.⁹⁹–¹⁰¹Helicobacter pylori provides another example of how disruption of mutually beneficial relationships may contribute to a range of immune and metabolic diseases. All of these factors provide potential avenues for immune modulation for disease prevention.

Modulating early immune development to promote immune regulation

As we learn more about the normal immune development and the environmental determinants, there will be more opportunities and more strategies to treat and prevent allergic disease. A detailed discussion of the merits of various allergy prevention strategies can be found in Chapters 16–22, but here we briefly consider the likely avenues based on emerging evidence.

Although the evidence has been limited, the most promising strategies to improve early colonization may lie in the strategic use of prebiotics and probiotics. So far, most studies using these products for allergy prevention have focused on improving postnatal colonization. Probiotics supplementation has generally been studied only from late pregnancy and/or the early postnatal period. Prebiotics have been investigated only in the postnatal period. Commencing the use of these products much earlier in gestation to modulate maternal colonization may be more effective in influencing important earlier phases of immune maturation in fetal life. In particular, prebiotic soluble fiber (oligosaccharides) promotes microbial diversity by stimulating the growth of commensals and providing the substrate for anti-inflammatory short-chain fatty acid (SCFA) production by bacteria. This is likely to have more global effects on gut homeostasis, restoring intestinal dysbiosis as well as maintaining epithelial barrier integrity.⁴⁶,¹⁰²

Studies of prebiotic oligosaccharides in pregnancy are also limited. In animal models, prebiotics in pregnancy alter colonization and metabolic homeostasis¹⁰³ and reduce eczema-like inflammation in offspring.¹⁰⁴ To our knowledge, the only randomized controlled trial to use prebiotics in human pregnancy was too small (n = 48) to reliably assess immune effects on the fetus or clinical effects, but achieved favorable changes in maternal gut microbiota.¹⁰⁵ In a clear proof of concept, preliminary studies (personal communication, Charles Mackay) provide tantalizing evidence that a high-fiber diet in pregnancy and lactation significantly reshapes bacterial ecology and prevents the allergic phenotype of the offspring, with reduced eosinophils, reduced allergic cytokine responses, and airway hyperresponsiveness. Direct administration of SCFA (acetate) had a similar effect as an important mediator of systemic dietary effects.

This highlights maternal nutrition as an important general strategy to promote immune health in all individuals. Other nutritional agents that are likely to be an important part of this approach include diets rich in n-3-PUFA, vitamin D, grains, fresh fruit and vegetables, and less processed foods.¹⁰⁶ This will also have benefits for metabolic regulation in addition to the likely benefits on immune function.¹⁰⁶ Other examples of general strategies to promote immune health include promoting breastfeeding, avoiding adverse exposures (such as cigarette smoke), and reducing stress.

On the other hand, there are also likely to be more targeted strategies in the future aimed at immunomodulation, which may focus on specific pathways and/or specific individuals. An example might be primary (prophylactic) use of immunotherapy, in particular, for high-risk groups, such as aeroallergen immunotherapy in children with food allergy, or strategies to improve barrier function in children with eczema. Vaccination strategies are also being explored. In collaboration with Barry Marshall (who first discovered H. pylori), we are currently exploring the immunomodulatory effects of attenuated or killed H. pylori strains and their capacity to reduce and prevent the symptoms of allergic disease.

An attractive option would be to model the asthma-protective farm effect into prophylactic or intervention strategies. A potential cocktail containing asthma-protective farm exposure may present a tantalizing option for asthma prevention. Lyophilized extracts of bacterial strains, in particular containing aeropathogenic bacteria, were suggested as protection against acute respiratory infections and possibly also for asthma.⁴⁶ Yet, how to optimize the microbiome to the most favorable, ideal colonization pattern still needs to be deciphered considering specific environmental exposure, among other factors.

Overall, for effective prevention, a combination of various factors from genetics to epigenetics, to different exposures such as nutrition, prebiotic, and smoking, and to orally administered bacterial extracts requires further investigation. Extending this, patient-individualized prevention taking into account specific control of environmental factors in patients with susceptible genotypes may prevent the manifestation of asthma.

Furthermore, intervention studies composed of a combination of factors may be more promising, because persistent asthma might result from complex interactions between respiratory viruses, allergens, and immune regulation.⁶,¹⁰⁷

This raises a series of issues that will become increasingly relevant as technologies evolve, including how to target interventions, how to identify specific groups at risk, and how to refine strategies according to the level of risk. For generic and noninvasive immunomodulatory strategies to improve early immune health, it can be strongly argued that a whole-population approach is both justified and logical because of the general health benefits that these are likely to have. Improving intestinal health is also beginning to fall into this category as better strategies and more evidence of the multisystem benefits continue to emerge. However, for other more costly, specific, or invasive strategies, a more targeted approach will be appropriate. For example, if allergen-specific immunotherapy is employed to prevent sensitization to common aeroallergens, this would be more appropriately targeted only to those at highest risk.

Conclusion

To keep healthy immune maturation in balance, environment combined with a given genotype participates in shaping early innate and adaptive immunity for healthy development. Although microbes are currently an attractive possibility influencing several facets of immune maturation, possibly during pregnancy, multifaceted regulation encompassing the mucosa, epithelium, gut, and immune system seems crucial. Together with currently known influences, a detailed insight into the key mechanisms mediated by microbial exposure can guide us toward novel and safe therapeutic and preventive strategies for healthy immune maturation.

References

1. Barker D.J. Fetal origins of coronary heart disease. BMJ. 1995;311:171–174.

2. Gluckman P.D, Hanson M.A, Cooper C, Thornburg K.L. Effect of in utero